Targeted cooling of tissue within a body

ABSTRACT

Devices and methods to cool a target tissue region inside the body are described. Fluid cooled below normal body temperature and blood at a normal body temperature are provided to the tissue region in proportions to cool the tissue region. A system for controlling the temperature of the target tissue region is disclosed. The system includes a catheter and a control system that controls the amount of cool fluid and blood provided to the tissue region. A catheter for providing cool fluid to the tissue region is also provided. The catheter includes a temperature sensor that extends to a location distal to the distal end of the catheter to sense the temperature of the tissue region.

TECHNICAL FIELD

This invention relates to cooling a target tissue region inside a body.

BACKGROUND

Myocardial ischemia, and in severe cases acute myocardial infarction(AMI), can occur when there is inadequate blood circulation to themyocardium due to coronary artery disease. Evidence suggests that earlyreperfusion of blood into the heart, after removing a blockage to bloodflow, dramatically reduces damage to the myocardium. However, thereestablishment of blood flow into the heart may cause a reperfusioninjury to occur. Reperfusion injury is believed to be due to the buildup of waste products on the myocardium during the time blood flow wasinadequate and the reaction of these waste products with oxygen in theblood when normal blood flow is reestablished. It is possible to reducereperfusion injury to the myocardium by cooling the myocardial tissueprior to reperfusion. Mild cooling of the myocardial tissue to atemperature between 28 and 36 degrees Celsius provides a protectiveeffect, likely by the reduction in the rate of chemical reactions andthe reduction of tissue activity and associated metabolic demands.

One method of cooling myocardial tissue is to place an ice pack over thepatient's heart. Another method involves puncturing the pericardium andproviding cooled fluid to a reservoir inserted into the pericardialspace near the targeted myocardial tissue. Cooling of the myocardialtissue may also be accomplished by perfusing the target tissue withcooled solutions. A catheter having a heat transfer element located inthe catheter's distal tip may also be inserted into a blood vessel tocool blood flowing into and through the heart. It is also possible tocool the myocardial tissue by supplying cool blood to the heart througha catheter placed in the patient's coronary sinus.

SUMMARY

The invention features devices and methods to cool a target tissueregion inside the body. In an aspect, the invention features a method ofcooling a target tissue region that includes providing fluid cooledbelow normal body temperature and blood at a normal body temperature tothe tissue region in proportions to cool the tissue region and maintain,for an extended period of time, the temperature of the tissue regionwithin a target temperature range that is below normal body temperature.

Implementations may include providing the cooled fluid and the blood atnormal body temperature to the tissue region simultaneously. Theproviding of the blood at normal body temperature to the tissue regionmay be performed using a catheter that occludes a vessel upstream fromthe tissue region and permits a selected amount of blood to flow througha lumen in the catheter and to the tissue region. The catheter may alsoperform the providing of cool fluid to the tissue region. The providingof blood to the tissue region can be performed by occluding a vesselupstream from the tissue region to restrict normal blood flow and thenremoving the occlusion to permit normal blood flow. A catheter may alsoprovide blood to the tissue region by partially occluding a vessel influid communication with the tissue region to permit a restricted amountof blood to flow to the tissue region. In other implementations, acatheter positioned in a vessel in fluid communication with the tissueregion may provide the fluid to the tissue region through a lumen thatextends longitudinally through the catheter, the lumen having a diameterof at least twenty thousandths of an inch.

In another aspect, the invention features a method of cooling a targettissue region inside a body that includes occluding a body vessel toprevent normal blood flow to the tissue region. While the body vessel isoccluded, cooled fluid is provided to the tissue region to cool thetissue region below normal body temperature. Normal blood flow to thetissue region is recommenced by removing the occlusion in the bodyvessel. Normal blood flow to the tissue region is prevented again byoccluding the body vessel before the temperature of the tissue regionreturns to normal body temperature. While the body vessel is occluded,cooled fluid is provided to the tissue region again to maintain thetemperature of the tissue region below normal body temperature.

In implementations, the body vessel may be occluded to prevent normalblood flow to the tissue region by inflating a balloon positioned in thevessel. In addition, a catheter positioned in a vessel at a locationupstream from the tissue region may provide the fluid to the tissueregion through a lumen extending longitudinally through the catheter,the lumen having a diameter of at least twenty thousandths of an inch.

In another aspect, the invention features a method of cooling a targettissue region inside a body that includes restricting normal blood flowto the tissue region so that only a desired amount of blood is providedto the tissue region. Cool fluid is provided to mix with the bloodprovided to the tissue region so as to cool the tissue region belownormal body temperature and to maintain, for an extended period of time,the temperature of the tissue region within a target tissue range thatis below normal body temperature.

In implementations, the providing of the blood at normal bodytemperature to the tissue region can be performed using a catheter thatoccludes a vessel upstream from the tissue region and permits a selectedamount of blood to flow through a lumen in the catheter and to thetissue region. The providing of blood at normal body temperature to thetissue region may also be performed using a catheter to partiallyocclude a vessel upstream from the tissue region and permit a selectedamount of blood to reach the tissue region. In other implementations, acatheter positioned in a vessel in fluid communication with the tissueregion may provide the fluid to the tissue region through a lumen thatextends longitudinally through the catheter, the lumen having a diameterof at least twenty thousandths of an inch.

Implementations of the various aspects of the invention may include oneor more other features. For example, the tissue region may be maintainedwithin the target temperature range that is below normal bodytemperature for a time period beyond the normal length of time a tissueregion is deprived of oxygenated blood during a heart procedure, orabout two minutes. The temperature of the tissue region can be within atarget temperature range of about 28 to 36 degrees Celsius. In addition,the providing of fluid and blood to cool the target tissue region can beperformed during a procedure to open a lesion in a vessel. Further, acontrol system may control the providing of fluid and blood to thetissue region to maintain the temperature of the tissue region belownormal body temperature.

In another aspect, the invention features a system for controlling thetemperature of a target tissue region inside the body. The systemincludes a catheter for providing cooled fluid to the tissue region andfor controlling normal blood flow to the tissue region. The system alsoincludes a control system that controls the amount of the cooled fluidand blood that the catheter provides to the tissue region so as to cooland to maintain, for an extended period of time, the tissue regionwithin a target temperature range that is below normal body temperature.

Implementations may include one or more of the following. The catheterfor providing fluid and controlling normal blood flow to the tissueregion may be a perfusion catheter. The catheter for providing fluid andcontrolling normal blood flow to the tissue region may also be a ballooncatheter. The catheter may include an infusion lumen for providing fluidto the tissue region that has a diameter of at least twenty thousandthsof an inch. The catheter may also include a temperature sensor that maybe advanced to a location distal to the catheter to measure thetemperature of the tissue region.

The control system may include a controller that controls the cooling ofthe tissue region without measuring the temperature of the tissueregion. The control system may also include a controller that controlsthe cooling of the tissue region without measuring the temperature ofthe cool fluid as it exits the catheter and is provided to the tissueregion. In addition, the system may have a temperature monitor thatreceives temperature information from a temperature sensor of thecatheter. In other implementations, the control system may include aninfusion pump to control the amount of cool fluid provided to the tissueregion. An inflation pump to inflate and deflate a balloon on thecatheter may also be provided.

In another aspect, the invention features a catheter for providing coolfluid to a tissue region inside a body. The catheter includes anelongated member having a lumen extending longitudinally therethrough toa distal end of the elongated member and a temperature sensor thatextends to a location distal to the distal end of the elongated memberto sense the temperature of the tissue region.

In implementations, the temperature sensor may be a thermocouple thathas two conductors of different material extending from a proximal endof the catheter and joined at a distal end to form a junction. Thetemperature sensor may sense the temperature of the tissue region bymeasuring the temperature of a vessel wall located distal to the distalend of the elongated member and adjacent to the target tissue region. Inother implementations, the temperature sensor may sense the temperatureof the tissue region by measuring the temperature of the cool fluidprovided to the tissue region distal to the distal end of the elongatedmember and adjacent to the target tissue region.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIGS. 1A and 1B are diagrams showing a side view of a distal end of aballoon catheter positioned in a coronary artery, shown incross-section, and illustrate a method of cooling a target tissue regionin the heart.

FIG. 2 is a cross-sectional view of the balloon catheter along the line2-2 shown in FIG. 1A.

FIG. 3 is a graph that shows the temperature of the target tissue regionduring the application of the cooling method illustrated in FIGS. 1A and1B.

FIG. 4 is a diagram of a side view of a distal end of a perfusioncatheter positioned in a coronary artery, shown in cross-section, andillustrates an alternative method of cooling a target tissue region inthe heart.

FIG. 5 is a cross-sectional view of the perfusion catheter along theline 5-5 shown in FIG. 4.

FIG. 6 is a graph that shows the temperature of the target tissue regionduring the application of the cooling method illustrated in FIG. 4.

FIG. 7 is a diagram of a side view of a proximal end of a catheter usedto cool a target tissue region and a control system connected to theproximal end of the catheter, the control system shown in block diagram.

Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

When an area of tissue has been deprived of oxygenated blood, such asduring acute myocardial infarction (AMI), the tissue region becomesischemic. The methods illustrated herein may be used to reduce theinjury to the ischemic tissue associated with reperfusion by providingcool fluid and blood at normal body temperature (typically 37 degreesCelsius) to the ischemic tissue region in proportions to cool andmaintain the temperature of the ischemic tissue region below normal bodytemperature for an extended period of time. By providing both cool fluidand normal blood flow to the tissue region, reperfusion injury can bereduced without extending the time that the tissue region is deprived ofoxygen.

FIGS. 1A and 1B illustrate a method of cooling a target tissue regionlocated within the heart. Referring to FIG. 1A, a distal portion 10 of aconventional balloon catheter is shown inside a coronary artery 16 of apatient's heart. Once positioned in the coronary artery 16, a balloon 20at the catheter's distal end 12 may be inflated to occlude the artery 16and prevent normal blood flow to a target tissue region 30. In someimplementations, the inflation of balloon 20 opens an occlusion in thecoronary artery 16. After normal blood flow has been stopped, cool fluid28, such as saline or ringers lactate, may be introduced into thecoronary artery 16 to cool the tissue region 30. Once the tissue region30 is cooled to a desired temperature, for example twenty-eight degreesCelsius, the balloon 20 may be deflated to resume normal blood flowthrough the coronary artery 16 as shown in FIG. 1B. The flow of bloodprovides oxygen to the tissue region, and in addition, increases thetemperature of the tissue. To maintain the temperature of the tissueregion 30 within a desired range for an extended period of time, thecooling method of FIGS. 1A and 1B may be repeated as required.

The catheter's distal end 12 may be positioned inside the coronaryartery 16 as shown in FIG. 1A by inserting the catheter's distal end 12into a vessel, such as the femoral artery, that provides access to thepatient's aorta 14. A guidewire (not shown) is advanced through theaorta 14 and into the desired vessel, which in the FIG. 1A example iscoronary artery 16. The catheter's distal end may then be advanced overthe wire through the aorta 14 and into the coronary artery 16. In someimplementations, a guide catheter may also be used to guide the catheterthrough the vessel.

The catheter 10 has an inflation lumen (not shown) that extendslongitudinally through the inside of the catheter 10 from the balloon 20to the catheter's proximal end (not shown in FIGS. 1A and 1B). Aninflation medium (gas or liquid) may be provided to and removed from theballoon 20 via the inflation lumen to inflate and deflate the balloon20. In this implementation, the balloon 20 is a conventional balloonsuited for use in heart vessels. For implementations in other locationsinside the body, a different balloon may be used. The inflation anddeflation of the balloon 20 may be controlled manually by the physician,or in some implementations, may be controlled automatically by a controlsystem located outside of the patient's body, as will be describedlater.

An infusion lumen (the lumen being shown in FIG. 2) extendslongitudinally through the catheter 10 from an opening 18 at thecatheter's distal end 12 to an opening at the catheter's proximal end(not shown in FIGS. 1A and 1B). The cool fluid 28 is provided to thecoronary artery 16 via the catheter's infusion lumen and thendistributed to the tissue region 30. The cool fluid may be provided atvarious temperatures and infusion rates, as will be described inconjunction with FIG. 3. The providing of the cool fluid 28 may beperformed manually by a physician or under the control of a controlsystem.

In the FIG. 1A example, the catheter's infusion lumen may have adiameter at its distal end 12 of either eighteen or twenty thousandthsof an inch, which is larger than the sixteen thousandths diameter thatis typically used in heart procedures. The use of this larger diameterinfusion lumen allows the cool fluid 28 to be provided to the tissueregion 30 at higher infusion rates without producing a “jetting” effect.The jetting effect occurs when fluid 28 is expelled from the catheter'sopening 18 at flow rates that are likely to cause damage to the vesselwalls. By increasing the diameter of the lumen from sixteen thousandthsto, for example, twenty thousandths, the flow velocity may be reduced byapproximately one-third. In implementations where catheters withinfusion lumen diameters smaller than twenty thousandths of an inch areused, the infusion rate of the fluid 28 may need to be reduced toprevent jetting.

A temperature sensor 22 is located near the catheter's distal end 12 tosense the temperature of the cool fluid 28 that is provided to thetissue region 30 through the opening 18. The temperature sensor providesfeedback to the physician performing the procedure or to an externalcontrol system that may be used to more precisely control the cooling ofthe tissue region 30. In the illustrated example, the temperature sensor22 is a thermocouple. The thermocouple is made up of two conductivewires (shown as a single wire 24 in FIGS. 1A and 1B for clarity) ofdissimilar materials that are insulated from each other. At a distalend, the wires 24 are connected together to form a junction 23 thatserves as a sensing element. This junction 23 produces a voltagedifference that is dependent on the temperature of the junction 23. Thewires 24 extend proximally from the junction 23, through an opening inthe distal end of the shaft, and through a lumen in the catheter shaft26 to an opening at the catheter's proximal end. An external device maybe connected to proximal ends of the two thermocouple wires 24 tomeasure the voltage difference between the wires 24, and then convertthat voltage measurement into an indication of the temperature of thejunction 23.

In one example, the wires 24 are approximately two thousands of an inchin diameter and may extend through the catheter's infusion lumen.Alternatively, the wires 24 may extend through an additional smallerlumen that extends longitudinally through the catheter's shaft 26 thatis sized specifically for the temperature sensor (both lumens shown inFIG. 2). The temperature sensor 22 may also be placed at differentlocations within the catheter to measure the temperature of the fluid 28being provided to tissue region 30 (not shown). Alternatively, thetemperature sensor 22 may be advanced distal to the catheter as shown inFIG. 1A. Positioning the temperature sensor 22 into the coronary arteryin this manner may allow the temperature of the tissue region 30 to bedetermined more precisely by providing the temperature of the fluid 28or the tissue in the coronary artery 16 near the tissue region 30.

In other implementations, other temperature sensors may be used, such asthermistors or other suitable temperature sensing mechanisms. Instead ofextending through the infusion lumen or guide wire lumen in thecatheter, the wires 24 may extend through an additional lumen in thecatheter shaft 26. Alternatively, the temperature sensor 22 may beomitted.

FIG. 2 is a cross-sectional view of the balloon catheter along the line2-2 shown in FIG. 1A. The FIG. 2 cross-section illustrates the relativediameters of the lumens that extend longitudinally through the catheterand the catheter's inflated balloon 20. In the FIG. 2 example, thecatheter includes an infusion lumen 40 and a sensor lumen 42. Theinfusion lumen may have a diameter of twenty thousandths of an inch,which would allow a physician to use an eighteen-thousandths guidewire,or a smaller guidewire if desired. In other examples, the infusion lumen40 may have a diameter of eighteen thousandths of an inch or smaller.The sensor lumen 42 may be approximately two thousandths of an inch indiameter to permit the passage of the temperature sensor wires throughthe catheter. The outer diameter of the catheter shaft 26 may beapproximately twenty-five thousands of an inch. However, the cathetershaft 26 may be larger in other examples. The outer diameter of theinflated balloon 20 may be approximately three millimeters in diameter.In implementations outside of the heart, a catheter having a largerdiameter shaft 26 and balloon 20 may be used.

With the aid of FIG. 3, the coordination of the inflation and deflationof the balloon 20, which controls normal blood flow in the coronaryartery 16 and the providing of cool fluid 28 to the tissue region 30will be described. FIG. 3 is a graph that illustrates the temperature ofthe target tissue region over time, namely, during the application ofthe cooling method of FIGS. 1A and 1B. The FIG. 3 graph is not based onactual results, but rather is intended to illustrate the cooling methodmore clearly. Before the cooling process is started, the temperature ofthe target tissue region is approximately thirty-seven degrees Celsius(normal body temperature), which is indicated by data point 50 on theFIG. 3 graph. In this example, the tissue region is maintained betweentwenty-eight and thirty-four degrees Celsius, which is referred to asthe target temperature range 62.

Once the distal end of the catheter is positioned in the coronary arteryand the guidewire is removed, the cooling process begins by inflatingthe balloon at data point 50 to prevent normal blood flow to the targettissue region. After the balloon has occluded the coronary artery, coolfluid is provided to the tissue region (as shown in FIG. 1A). In thisexample, the cool fluid is provided at a temperature of approximatelyfifteen degrees Celsius and at an infusion rate of twenty-five ml/min.The providing of cool fluid cools the tissue from normal bodytemperature to the low temperature in the target temperature range 62,twenty-eight degrees Celsius, as indicated by data point 52.

During the initial cooling of the tissue between data points 50 and 52,the coronary artery is occluded by the balloon and the tissue continuesto be deprived of oxygenated blood. At the fluid temperature andinfusion rate in this example, the cooling of the tissue to twenty-eightdegrees occurs in approximately sixty seconds. This time period is lessthan two minutes, which is generally the maximum amount of time that atissue region should be deprived of oxygenated blood during a heartprocedure. The methods of FIGS. 1 and 4 allow cooling beyond the twominute benchmark by providing cool fluid and oxygenated blood inproportions to maintain the temperature of the tissue region belownormal body temperature.

Once the tissue is cooled to the low temperature in the targettemperature range, the balloon may be deflated (as shown in FIG. 1B) toprovide normal blood flow to the tissue region. In the FIG. 3 example,the balloon is deflated at data point 52. The flow of blood to thetissue region at normal body temperature and the heat provided byadjacent body tissues cause the temperature of the tissue region torise. After approximately sixty seconds of normal blood flow, thetemperature of the tissue region will return to normal body temperature.Thus, in implementations where the cooling of the tissue region is to bemaintained for an extended period of time, such as the example of FIG.3, normal blood flow to the tissue region is prevented once the tissuetemperature rises to the high temperature of thirty-four degrees in thetarget temperature range 62, and cool fluid is once again provided tocool the tissue region.

In the FIG. 3 example, the inflation of the balloon and the providing ofcool fluid to the tissue region occurs again at data point 54. The timeelapsed between data points 52 and 54 is approximately thirty seconds.At data point 54, cool fluid is again provided to the tissue region, andthe tissue is once again cooled to approximately twenty-eight degrees asindicated by data point 56. In this example, the cool fluid providedduring the period between data points 54 and 56 is provided at the sametemperature (fifteen degrees) and infusion rate (twenty-five ml/min) asduring the initial cooling period between data points 50 and 52. Inother implementations, however, the cool fluid may be provided at adifferent temperature and infusion rate, which may change the rate ofcooling.

After the tissue region is cooled to approximately twenty-eight degrees,the balloon is deflated and normal blood flow to the tissue is resumed.The flow of blood at normal body temperature to the tissue region causesthe temperature of the tissue region to rise once again. When thetemperature of the tissue region increases to approximately thirty-fourdegrees, the balloon is inflated and normal blood flow is preventedstarting at data point 58. Cool fluid is provided once again to cool thetissue region. The process of cooling and resuming normal blood flow maycontinue for an extended period of time. Alternatively, cool fluid couldbe continuously infused during the balloon inflate-deflate cycle; thiswould allow for less temperature variation while providing oxygenatedperfusion.

The tissue cooling time may be limited by the total amount of cool fluidthat is provided to tissue region during the cooling procedure.According to standard practice, the maximum amount of fluid that shouldbe injected into the body during the procedure is approximately oneliter. At the infusion rate of the cool fluid in the FIG. 3 example, thecooling procedure may be performed for approximately sixty minutesbefore a liter of cool fluid is provided to the body. In otherimplementations, the total cooling time may be extended by providingcool fluid at a temperature below fifteen degrees at a lower infusionrate. However, fluid temperatures that are too low may cause a spasm ofthe artery or arrhythmias. Once the tissue has been cooled for adesirable period of time, the balloon is deflated and the temperature ofthe tissue region will return to normal body temperature as indicated bydata point 60. In some examples, cool fluid may be provided to thetissue region in addition to normal blood flow to gradually bring thetemperature of the tissue region back to normal body temperature. Inthis example, the target warming rate is between one-half and twodegrees Celsius per minute. Warming the tissue region at a rate abovetwo degrees Celsius per minute may result in fibrillation.

FIG. 4 shows an alternative method of cooling a target tissue regioninside the heart. In the FIG. 4 example, a distal portion 100 of aconventional perfusion catheter is positioned into a coronary artery 116of the heart to cool a target tissue region 130. Once a distal end 112of the catheter is positioned in the artery 116, a balloon 120 isinflated to prevent normal blood flow to the target tissue region 130,and in some implementations, to open an occlusion of the coronary artery116. Cool fluid 128 is provided from an opening 118 at the catheter'sdistal end 112 to the target tissue region 130. Blood that enters hole124 located proximal to the balloon 120 and that exits the cathetershaft 110 distal to the balloon 120 is also provided to the tissueregion 130. By providing a mixture of cool fluid 128 and the patient'sblood, the tissue region 130 may be simultaneously cooled and suppliedwith oxygen.

An inflation lumen (not shown) extends longitudinally through thecatheter from the balloon 120 to the catheter's proximal end (not shownin FIG. 4). The balloon 120 may be inflated and deflated by providingand removing an inflation medium via the inflation lumen, as isconventional. In this implementation, the balloon 120 is a conventionalballoon suited for use in the heart. For implementations in otherlocations inside the body, a different balloon may be used. Theinflation and deflation of the balloon 20 may be controlled manually bythe physician, or in some implementations, may be controlledautomatically by an external control system.

An infusion lumen (the lumen being shown in FIG. 5) extendslongitudinally through the catheter from an opening 118 at thecatheter's distal end 112 to an opening at the catheter's proximal end(not shown). The cool fluid 128 is provided to the tissue region 130 viathe catheter's infusion lumen. The cool fluid may be provided at varioustemperatures and infusion rates, as will be described in conjunctionwith FIG. 6. In one example, the catheter's infusion lumen may be twentythousandths of an inch in diameter at the catheter's distal end 112. Thetwenty thousandths diameter may likely prevent the jetting effect thatmay occur at smaller infusion lumen diameters, as discussed previously.A physician can manually provide the cool fluid 128 to the tissue region130, or a control system may be used.

A perfusion lumen (the lumen being shown in FIG. 5) in the cathetershaft 110 extends longitudinally through the catheter distal end 100between the holes 124 and 126. The size and shape of the hole 124determines the amount of blood that enters the perfusion lumen andbypasses the inflated balloon 120 as indicated by the arrows. In theFIG. 4 implementation, the perfusion lumen of catheter 100 allows bloodto bypass the balloon 120 at a rate of fifteen to thirty ml/min. Becausethe approximate amount of blood flow to the target tissue 130 is known,an appropriate amount of cooled fluid 128 can be provided to the tissueregion 130 via the inflation lumen to maintain the temperature of thetissue region 130 at a desired temperature below normal bodytemperature.

A temperature sensor 122 is located at the catheter's distal end 112 tosense the temperature of the cool fluid 128 as the fluid 128 exits theinfusion lumen through the opening 118 and to provide feedback to thephysician performing the procedure. In this example, the temperaturesensor 122 is a thermocouple. In other implementations, othertemperature sensors may be used, such as thermistors or other suitabletemperature sensing mechanisms. Further, the temperature sensor may beextended distal to the catheter opening 118, as shown in FIGS. 1A and1B, or positioned at other locations within the catheter shaft tomeasure the temperature of the fluid. In other implementations, thetemperature sensor 122 may be omitted.

The perfusion catheter of the FIG. 4 example may be used tosimultaneously provide cool fluid and blood to the tissue region. Inother implementations, a conventional balloon catheter, such as thecatheter shown in FIGS. 1A and 1B, may be used to provide the sameeffect. In the FIG. 1A example, the balloon 20 was inflated tocompletely occlude the coronary artery 16 and prevent all blood flow tothe tissue region 30. If the balloon 20 were only partially inflated, aspecified amount of blood could flow around the partially inflatedballoon 20 and be provided to the tissue region 130.

FIG. 5 is a cross-sectional view of the perfusion catheter along theline 5-5 shown in FIG. 4. The FIG. 5 cross-section illustrates therelative diameters of the lumens that extend longitudinally through thecatheter and the catheter's balloon 120. In the FIG. 5 example, thecatheter includes a perfusion lumen 140 and an infusion lumen 142. Theperfusion lumen may have a diameter of approximately forty-seventhousandths of an inch, which perfuses blood at a rate of approximatelyfifteen to thirty ml/min. In other examples, a larger or smallerdiameter perfusion lumen may be used to increase or decrease the amountof blood perfused to the tissue region. The infusion lumen 142 may havean inner of twenty thousandths of an inch, which would allow a physicianto use an eighteen-thousandths guidewire, or a smaller guidewire ifneeded. In other examples, the infusion lumen 40 may have an innerdiameter of eighteen thousandths of an inch or smaller.

In the FIG. 5 example, the wires 124 extending from the temperaturesensor 122 (not shown in FIG. 4) are located next to the infusion lumen142. In other examples, the catheter may include a sensor lumen, asshown in FIG. 2, or the wires 124 may extend longitudinally in adifferent location within the catheter. The outer diameter of thecatheter shaft 110 may be sixty-five thousands of an inch. However, thecatheter shaft 26 may be larger or smaller in other examples. The outerdiameter of the inflated balloon 120 may be approximately threemillimeters. In other implementations, a catheter having a larger orsmaller diameter balloon 20 may be used.

FIG. 6 is a graph that illustrates the temperature of the target tissueregion during the application of the cooling method of FIG. 4, for whichexample results are shown. The FIG. 6 graph is not based on actualresults, but rather is intended to simply illustrate the cooling methodmore clearly. Before the cooling process is started, the target tissueregion is at normal body temperature, as indicated by data point 150. Inthis example, the tissue region is cooled to a target temperature ofthirty degrees Celsius and is maintained at that temperature for theduration of the procedure.

The cooling method of FIG. 6 begins by inflating the balloon at datapoint 150 to prevent normal blood flow to the tissue region. Thecatheter's perfusion lumen permits a controlled amount of blood to beprovided to the tissue region through the hole in the catheter shaft,for example twenty ml/min. In other implementations, perfusion cathetersthat permit more or less blood to flow to the tissue region may be used.Once the distal end of the catheter is positioned and blood flow to thetissue region has been restricted, cool fluid is provided to the tissueregion. In this example, the temperature of the cool fluid provided tothe tissue region is approximately fifteen degrees Celsius and isinfused at a rate of twenty-five ml/min. The mixture of cool fluid andblood cools the tissue region to approximately thirty degrees Celsius,as indicated by data point 152. At this temperature and infusion rate,the tissue will cool from normal body temperature to thirty degreesCelsius in approximately sixty seconds.

Once the tissue region is cooled to the target temperature 154, thetemperature of the cool fluid provided to the tissue region may beincreased to prevent further cooling below the target temperature 154.In the FIG. 6 example, the temperature of the cool fluid provided to thetissue region is increased to thirty degrees at data point 152.Alternatively, further cooling below the target tissue temperature 154may be prevented by reducing the infusion rate of the cool fluid ratherthan increasing fluid temperature. In other implementations, both thetemperature and the infusion rate may be adjusted.

The mixing of normal blood and cool fluid to maintain the target tissuetemperature 154 may be continued for as long as desired. In someapplications, however, the maximum amount of fluid that may be providedto the body during the cooling procedure is approximately one liter. Atthe infusion rate of the cool fluid in the FIG. 6 example, the coolingprocedure may be performed for approximately forty minutes before aliter of cool fluid is provided to the body. In other implementations,the total cooling time may be extended by providing cool fluid at alower temperature and at a lower infusion rate.

Once the tissue region has been cooled for the desired amount of time,the balloon may be deflated and normal blood flow to the tissue regionmay be resumed. The deflation of balloon 120 occurs at point 156 on theFIG. 6 graph. After normal blood flow is resumed, the temperature of thetarget tissue region rises until it reaches normal body temperature atdata point 158. As discussed previously, in some examples additionalcool fluid may be provided to the tissue region after resuming normalblood flow to gradually bring the temperature of the tissue region backto normal body temperature at the target warming rate.

In the examples shown in FIGS. 1-6, the temperature of the cool fluidprovided to cool the tissue region may range from twelve to thirty-sixdegrees Celsius. Further, in the implementations where infusion lumenshaving a diameter of twenty thousandths of an inch are used, the fluidmay be provided at an infusion rate of thirty ml/min without damagingthe vessel walls. Alternatively, fluid may be provided at higher ratesin implementations where the catheter includes a diffuser (i.e., holesor slots) at its distal end through which the fluid exits. The timerequired to cool the tissue region in the various examples may bereduced by providing fluids at lower temperatures or at higher infusionrates. Conversely, providing cool fluid at temperatures highertemperatures or lower infusion rates may increase the time required forthe cool fluid to cool the tissue region. The upper and lower limit ofthe temperature range in the example of FIGS. 1-3 and the targettemperature of the FIG. 4-6 example may be increased or decreased asdesired. However, temperatures below twenty-eight degrees Celsius maycause complications such as arterial spasm or fibrillation.

The cooling methods illustrated in FIGS. 1-6 may be performed in avessel that contains a lesion or blockage and is being treated with apercutaneous transluminal coronary angioplasty. Alternatively, themethod may be performed in a vessel that does not require suchtreatment. For procedures where the methods are performed in a vesselthat does not require the repair of a lesion, the cooling method can beutilized to cool a target tissue region that is adjacent to the tissuesin fluid communication with the particular vessel in which the method isbeing performed. The cooling method may also be used to cool otherorgans in the body, such as the brain, kidney, and liver.

The cooling methods previously described in FIGS. 1A, 1B, and 4 may beperformed manually, or automatically with the aid of an external controlsystem. FIG. 7 shows a proximal end of a catheter 180 connected to acontrol system 200. In this example, the control system 200 includes acontroller 202, a fluid pump 204, a heat exchanger 206, an inflationpump 208, a temperature monitor 210, and a patient monitor 212. Thecontroller 202 controls the operation of the fluid pump 204 and the heatexchanger 206, which together dictate the temperature and rate of coolfluid provided to the tissue region via catheter 180. The controller 202also controls the inflation pump 208, which dictates the amount ofnormal blood flow to the tissue region by inflating and deflating thecatheter's balloon. Through the control of these external devices, thecontroller 202 may cool the tissue region and maintain the cooltemperature for an extended period of time.

Catheter 180 has an adapter 182 that has two ports 184 and 186. The port184 provides access to an inflation lumen that extends longitudinallythrough the catheter to a balloon at the catheter's distal end (notshown in FIG. 7). An inflation medium may be provided to the balloon viathe inflation lumen to inflate and deflate the balloon. The port 186provides access to an infusion lumen that also extends longitudinally toan opening at the catheter's distal end. Cooled fluid may be provided tothe target tissue region via the infusion lumen. In the FIG. 7 example,the catheter 180 is a balloon catheter. In other implementations, thecatheter 180 may be a perfusion catheter or other catheter suitable forcooling a target tissue region in accordance with the methods describedherein.

In the FIG. 7 implementation, the controller 202 receives input from theother devices in the control system 200 and uses that information, inaddition to patient data input by a physician, to coordinate theproviding of fluid and the flow of normal blood to the tissue region.For example, the fluid pump 204 provides the controller 202 with therate at which the fluid 214 is infused through the catheter 180 to thetissue region. The temperature monitor 210 inputs the temperature of thefluid 214 as it exits the distal end of the catheter or the temperatureof the fluid distal to the end of the catheter 180. In implementationswhere a temperature monitor 210 is not used, the heat exchanger 206 mayprovide the temperature of the fluid 214 before it is infused throughthe catheter 180. The inflation pump 208 provides the controller 202with the pressure of the balloon. From the information provided by theinflation pump 208, the controller 202 can determine whether the balloonis inflated, and if so, whether the balloon is fully inflated or onlypartially inflated. The patient monitor 212 provides the patient'sphysiologic information to the controller 202, such as the patient'sheart rate, heart rhythm, blood pressure, blood oxygen level, etc. Fromthis information, the controller 202 can alert the physician if thepatient is experiencing complications and may adjust the coolingprocedure accordingly.

The controller 202 may also receive information about the procedure tobe performed, such as the specific cooling technique to be applied, thetype of catheter that is being used (including the diameter of theinflation lumen and size of the balloon), the vessel in which thecooling technique will be applied, the type of fluid that is beingprovided to the target tissue region, the target temperature range, thetotal length of the procedure, and the total volume of fluid to beinfused. In certain applications, the temperature of the target tissueregion cannot be directly measured during the cooling procedure. This isoften the case when the target tissue region cannot be readily accessedwithout performing a more invasive procedure. In implementations wherethe temperature of the tissue region can be measured during the coolingprocedure, the control system 200 may include a second temperaturemonitor that provides the temperature of the target tissue region to thecontroller 202.

In implementations where the temperature of the target tissue regioncannot be measured, the controller 202 may be provided with control dataobtained from bench or pre-clinical testing that allows the controller202 to determine the temperature of the target tissue region based onthe temperature and infusion rate of the fluid 214 and the amount ofnormal blood flow provided to the tissue region. For example, thecontrol data may include the rate of temperature changes in anassortment of tissue regions inside the body when cool fluids areprovided at varied temperatures and infusion rates. This information maybe provided to the controller 202 for a variety of different fluids thatmay be used to cool the body. The control data may also include the rateof temperature change in the tissue region when normal blood flow isprovided or when only heat from surrounding tissue is provided to thetissue region. Parameters for cycling the inflation of the balloonduring the various stages of the cooling procedure to provide normalblood flow to the tissue region may also be included.

The control data may also include procedural constraints, such as aminimum temperature of the target tissue region and the maximum rate atwhich the tissue region may be cooled or allowed to warm. With respectto the control of the catheter's balloon, the control data may indicatethe size of the various body vessels and the required pressure toproperly inflate the balloon. Additionally, the maximum infusion rateand total amount of a cool fluid injected into the body during aprocedure may also be provided. These are only some examples of theinformation that may be provided to the controller 202 in the form ofcontrol data to control the cooling of the target tissue region. Otherdata may be provided as necessary.

After receiving the patient data and the inputs from the other devicesin the control system 200 described above, the controller 202 processesthis information in accordance with the control data previouslydescribed and provides output to the fluid pump 204, the heat exchanger206, and the inflation pump 208 to control the temperature of the tissueregion. During the procedure, the controller 202 continually monitorsthese inputs and adjusts the outputs in accordance with the coolingprocedure being performed. In the FIG. 7 implementation, the controller202 is a digital or analog feedback controller. In otherimplementations, a different type of controller may be used.

In the FIG. 7 implementation, the fluid used for infusion is fluid 214.However, any fluid that is biocompatible may be infused for cooling.Additionally, the fluid 214 may contain additives and may be changedthroughout the cooling procedure. The fluid 214 may be infused throughthe infusion lumen of the catheter by a conventional pump 204. Forexample, a positive displacement pump may be used to provide thepressure necessary to urge the fluid 214 through the narrow infusionlumen of the catheter. In other implementations the pump 204 may bereplaced with a raised bag containing the fluid 214 with an inflatablepressure cuff to control the infusion rate of the fluid 214. The fluidpump 204 includes an infusion monitor to monitor the pressure and flowrate of the fluid 214 through the infusion lumen of the catheter 180 andprovide that information to the controller 202.

A conventional heat exchanger may be used to cool the fluid 214. In thisimplementation, the heat exchanger is controlled by the controller 202by processing the information received from the temperature monitor 210and the controller's control data. The temperature monitor 210 receivesinformation from a temperature sensor in the catheter, such as thetemperature sensor 22 shown in FIG. 1A, or the temperature sensor 122shown in FIG. 4. Based on the information provided by the temperaturemonitor 210, the heat exchanger 206 can be used to cool or warm thefluid 214 provided to the target tissue region. In implementations wherea temperature sensing device is not used to measure the temperature ofthe fluid 214 provided to the tissue region, the temperature monitor 210may be omitted.

The inflation medium 216 may be infused through the inflation lumen ofthe catheter by a conventional pump 208. The inflation medium may beeither a gas or a liquid. In one implementation, the inflation pump 208is a positive displacement pump. In other implementations, the pump 208may be a pneumatic or hydraulic pump. In implementations where thecatheter's balloon is not inflated and deflated to control the flow ofblood to the tissue region, such as the method shown in FIGS. 4 and 5,the inflation pump may be omitted and the inflation and deflation of theballoon may be performed manually.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1. A method of cooling a target tissue region inside a human body, themethod comprising: providing non-oxygenated fluid cooled below normalhuman body temperature of about 37 degrees Celsius and oxygenated bloodat a normal human body temperature of about 37 degrees Celsius to thetissue region in proportions to cool the tissue region and maintain, foran extended period of time greater than two minutes, the temperature ofthe tissue region within a target temperature range that is one to ninedegrees Celsius below the normal body temperature, wherein theoxygenated blood is provided so that any continuous period of timeduring which the tissue region is deprived of oxygenated blood while thenon-oxygenated fluid is being provided continues for less than twominutes, and further wherein the providing of the blood at the normalbody temperature to the tissue region is performed using a catheter thatoccludes a vessel upstream from the tissue region and permits a selectedamount of blood to flow through a lumen in the catheter and to thetissue region.
 2. The method of claim 1 wherein the cooled fluid and theblood at normal body temperature are provided to the tissue regionsimultaneously.
 3. The method of claim 1 wherein the catheter alsoperforms the providing of cool fluid to the tissue region.
 4. The methodof claim 1 wherein a catheter positioned in a vessel in fluidcommunication with the tissue region provides the fluid to the tissueregion through a lumen that extends longitudinally through the catheter,the lumen having a diameter of at least twenty thousandths of an inch.5. The method of claim 1 wherein the temperature of the tissue region ismaintained within the target temperature range that is below normal bodytemperature for a time period beyond the normal length of time a tissueregion is deprived of oxygenated blood during a head procedure.
 6. Themethod of claim 5 wherein the normal length of time a tissue region isdeprived of oxygenated blood during a heart procedure is about twominutes.
 7. The method of claim 1 wherein the temperature of the tissueregion is maintained within the target temperature range for at leastabout two minutes.
 8. The method of claim 1 wherein the providing offluid and blood to cool the target tissue region is performed during aprocedure to open a lesion in a vessel.
 9. The method of claim 1 whereina control system controls the providing of fluid and blood to the tissueregion.
 10. A method of cooling a target tissue region inside a humanbody, the method comprising: occluding a human body vessel to preventnormal blood flow to the tissue region; providing, while the body vesselis occluded, cooled fluid to the tissue region to cool the tissue regionbelow normal body temperature of about 37 degrees Celsius; recommencingnormal blood flow to the tissue region by removing the occlusion in thebody vessel; preventing normal blood flow to the tissue region again byoccluding the body vessel before the temperature of the tissue regionreturns to normal body temperature; and providing, while the body vesselis occluded, cooled fluid to the tissue region again to maintain thetemperature of the tissue region below the normal body temperature ofabout 37 degrees Celsius.
 11. The method of claim 10 wherein the bodyvessel is occluded to prevent normal blood flow to the tissue region byinflating a balloon positioned in the vessel.
 12. The method of claim 10wherein a catheter positioned in a vessel at a location upstream fromthe tissue region provides the fluid to the tissue region through alumen extending longitudinally through the catheter, the lumen having adiameter of at least twenty thousandths of an inch.
 13. The method ofclaim 10 wherein a control system controls the occluding of the bodyvessel and the providing of cooled fluid to the tissue region tomaintain the temperature of the tissue region below normal bodytemperature.
 14. A method of cooling a target tissue region inside ahuman body, the method comprising: restricting normal blood flow to thetissue region so that only a desired amount of blood is provided to thetissue region; and providing cool fluid to mix with the blood providedto the tissue region so as to cool the tissue region below normal bodytemperature of about 37 degrees Celsius and to maintain, for an extendedperiod of time greater than two minutes, the temperature of the tissueregion within a target temperature range that is one to nine degreesCelsius below the normal body temperature of about 37 degrees Celsius,further wherein the providing of the blood at normal body temperature tothe tissue region is performed using a catheter that occludes a vesselupstream from the tissue region and permits a selected amount of bloodto flow through a lumen in the catheter and to the tissue region. 15.The method of claim 14 wherein the temperature of the tissue region ismaintained within the target temperature range that is below the normalbody temperature for a time period beyond the normal length of time atissue region is deprived of oxygenated blood during a heart procedure.16. The method of claim 15 wherein the normal length of time a tissueregion is deprived of oxygenated blood during a heart procedure is abouttwo minutes.
 17. The method of claim 14 wherein the temperature of thetissue region is maintained within the target temperature range for atleast about two minutes.
 18. The method of claim 14 wherein a catheterpositioned in a vessel in fluid communication with the tissue regionprovides the fluid to the tissue region through a lumen that extendslongitudinally through the catheter, the lumen having a diameter of atleast twenty thousandths of an inch.
 19. The method of claim 14 whereina control system controls the providing of fluid to the tissue region tomaintain the temperature of the tissue region below normal bodytemperature.
 20. A method of cooling a target tissue region inside ahuman body, the method comprising: providing non-oxygenated fluid cooledbelow normal human body temperature of about 37 degrees Celsius andoxygenated blood at the normal human body temperature of about 37degrees Celsius to the tissue region in proportions to cool the tissueregion and maintain, for an extended period of time greater than twominutes, the temperature of the tissue region within a targettemperature range that is one to nine degrees Celsius below the normalhuman body temperature of about 37 degrees Celsius, wherein theoxygenated blood is provided so that any continuous period of timeduring which the tissue region is deprived of oxygenated blood while thenon-oxygenated fluid is being provided continues for less than twominutes, and further wherein the providing of the blood at the normalbody temperature to the tissue region is performed by occluding a vesselupstream from the tissue region to restrict normal blood flow and thenremoving the occlusion to permit normal blood flow.
 21. The method ofclaim 20 wherein the cooled fluid and the blood at normal bodytemperature are provided to the tissue region simultaneously.
 22. Themethod of claim 20 wherein the catheter also performs the providing ofcool fluid to the tissue region.
 23. The method of claim 20 wherein acatheter positioned in a vessel in fluid communication with the tissueregion provides the fluid to the tissue region through a lumen thatextends longitudinally through the catheter, the lumen having a diameterof at least twenty thousandths of an inch.
 24. The method of claim 20wherein the temperature of the tissue region is maintained within thetarget temperature range that is below normal body temperature for atime period beyond the normal length of time a tissue region is deprivedof oxygenated blood during a heart procedure.
 25. The method of claim 24wherein the normal length of time a tissue region is deprived ofoxygenated blood during a heart procedure is about two minutes.
 26. Themethod of claim 20 wherein the temperature of the tissue region ismaintained within the target temperature range for at least about twominutes.
 27. The method of claim 20 wherein the providing of fluid andblood to cool the target tissue region is performed during a procedureto open a lesion in a vessel.
 28. The method of claim 20 wherein acontrol system controls the providing of fluid and blood to the tissueregion.